Following up h e finQng that the non-imidazole drug clozapine shows a considerable histamine H3 receptor antagonistic activiryl 1.21 , a scrim of analogues and metabolites (clorapinc-N-oxide. and N-desmcthylclozapine) were tested for thcir affinity towards thc H3 receptor using the radiolabelled H, antagonist ['-sl]-idophmpropit. Qualitative structure affinity relationships are derived for the tested compounds. In the clozapine molccule four structurally differcnt moieties may be considered. In comparison with the affinity for the H3 receptor shown by clozapine. the following main conclusions can be drawn: The 4-piperazinyl region does not dlow substituents longer than a CH3 or electronegative atoms such as an 0 (as in clozapine-N-oxide); the lack of the CH3 group ( ~t s in N-desmethylclozapine) also reduccs the affinity for H3 receptors. Substitutions at the 5diazepine position do not drastically alter thc aftinity for the H3 receptor. although a basic Nmgen is favoured ovec CH2, 0, or S. The 8 position in ring I is an important modulatory site for H3 affinity; electronegative substitwnts such a\ chloro and fluoro in this aromatic ring increaw rhe affinity. When [hex substituents are. however. present at position Xz in the ring, they disable binding to the H3 rcccptor. The two major clozapiw metabolites (clompine-N-oxide, and N-desmethylclozapine) will not be responsible for a possible contribution of the H3 receptor antagonism t o the clinical profile of clozapine.
Clozapine is a so called atypical antipsychotic agent of the tricyclic dibenzodiazepine class, the clinical efficacy of which is thought to be associated with both dopaminergic and serotonergic systemst8]. Compared with classical neuroleptics, the affinity of clozapine for the dopamine D2 receptor is lowr9, lo]. On the other hand, clozapine's affinity for dopamine Dl and D4 receptors, which occur in the mesolimbic rather than neostriatal areas is relatively high I1 '-I3]. Clozapine has also high affinity for the histamine H1 receptor and al-adrenergic receptor, and moderate affinity for the a2 and P-adrenergic receptors . A moderate affinity of clozapine for the histamine H receptors in rat cerebral cortex was recently reported", 2? Functionally, clozapine acts as an H3 antagonist against the H3 receptor mediated inhibition of the electrically evoked release of [3H]-noradrenaline in slices of mouse brain cortex ['], and the H3 receptor mediated inhibition of the electrically stimulated release of [3H]-5-hydroxytryptamine in slices of rat brain cortexr2].
In the present paper we report on the binding of clozapine main metabolites and several other analogues of clozapine to the histamine H3 receptor. None of the investigated compounds carries an imidazole ring which has been reported to be important for binding to the H3 receptor. Structure affinity relationships for the binding of non-imidazole compounds to the histamine H3 receptor are presented.